Bio-field effect transistor device

ABSTRACT

A bioFET device includes a semiconductor substrate having a first surface and an opposite, parallel second surface and a plurality of bioFET sensors on the semiconductor substrate. Each of the bioFET sensors includes a gate formed on the first surface of the semiconductor substrate and a channel region formed within the semiconductor substrate beneath the gate and between source/drain (S/D) regions in the semiconductor substrate. The channel region includes a portion of the second surface of the semiconductor substrate. An isolation layer is disposed on the second surface of the semiconductor substrate. The isolation layer has an opening positioned over the channel region of more than one bioFET sensor of the plurality of bioFET sensors. An interface layer is disposed on the channel region of the more than one bioFET sensor in the opening.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.15/661,969, filed on Jul. 27, 2017, which is incorporated herein byreference in its entirety.

BACKGROUND

Biosensors are devices for sensing and detecting biomolecules andoperate on the basis of electronic, electrochemical, optical, andmechanical detection principles. Biosensors that include transistors aresensors that electrically sense charges, photons, and mechanicalproperties of bio-entities or biomolecules. The detection can beperformed by detecting the bio-entities or biomolecules themselves, orthrough interaction and reaction between specified reactants andbio-entities/biomolecules. Such biosensors can be manufactured usingsemiconductor processes, can quickly convert electric signals, and canbe easily applied to integrated circuits (ICs) andmicroelectromechanical systems (MEMS).

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the present disclosure are best understood from the followingdetailed description when read with the accompanying figures. It isnoted that, in accordance with the standard practice in the industry,various features are not drawn to scale. In fact, the dimensions of thevarious features may be arbitrarily increased or reduced for clarity ofdiscussion.

FIG. 1 illustrates components of a sensing device, according to someembodiments.

FIG. 2 illustrates a cross-sectional view of an exemplary dual-gateback-side sensing FET sensor, according to some embodiments.

FIG. 3 is a circuit diagram of a plurality of FET sensors configured inan exemplary addressable array, according to some embodiments.

FIG. 4 is a circuit diagram of an exemplary addressable array of dualgate FET sensors and heaters, according to some embodiments.

FIGS. 5A and 5B illustrate a cross-sectional view of an exemplary dualgate back-side sensing FET sensor and a non-sensing FET, according tosome embodiments.

FIG. 6A illustrates a layout of a dual gate back-side sensing FET sensorand a non-sensing FET, according to some embodiments.

FIG. 6B illustrates a circuit representation of the layout of a dualgate back-side sensing FET sensor and a non-sensing FET, according tosome embodiments.

FIG. 7A illustrates a layout of multiple pixels of dual gate back-sidesensing FET sensors and non-sensing FETs with a common sensing well,according to some embodiments.

FIG. 7B illustrates a side view of dual gate back-side sensing FETsensors in a row with the common sensing well, according to someembodiments.

FIG. 7C illustrates a circuit representation of the layout of multiplepixels of dual gate back-side sensing FET sensors and non-sensing FETs,according to some embodiments.

FIG. 8A illustrates a layout of multiple dual gate back-side sensing FETsensors and non-sensing FETs with a common sensing well, according tosome embodiments.

FIG. 8B illustrates a circuit representation of the layout of dual gateback-side sensing FET sensors and non-sensing FETs, according to someembodiments.

FIG. 9 illustrates a flow diagram of an exemplary method of fabricatinga plurality of dual gate back-side sensing FET sensors, according tosome embodiments.

FIG. 10 illustrates an example layout of a biosensing chip, according tosome embodiments.

FIGS. 11A-11E illustrate stages of a fabrication process for apiezoelectric mixer, according to some embodiments.

FIG. 12 illustrates the integration of a mixer with an exemplary dualgate back-side sensing FET sensor, according to some embodiments.

FIG. 13 illustrates a cross-sectional view of an exemplary dual gateback-side sensing FET sensor acting as a pH sensor, according to someembodiments.

FIGS. 14A and 14B illustrate using the dual gate back-side sensing FETsensor as a pH sensor, according to some embodiments.

FIG. 15 illustrates a cross-sectional view of an exemplary dual gateback-side sensing bioFET detecting DNA, according to some embodiments.

FIG. 16A illustrates binding mechanics of DNA on a receptor surface,according to some embodiments.

FIG. 16B illustrates a change in threshold voltage for an exemplary dualgate back-side sensing bioFET based on matched analyte binding,according to some embodiments.

FIG. 17 illustrates a cross-sectional view of an exemplary dual gateback-side sensing bioFET having antibodies immobilized on its sensinglayer, according to some embodiments.

FIG. 18 illustrates binding mechanics of antigens and antibodies on areceptor surface, according to some embodiments.

DETAILED DESCRIPTION

The following disclosure provides many different embodiments, orexamples, for implementing different features of the provided subjectmatter. Specific examples of components and arrangements are describedbelow to simplify the present disclosure. These are, of course, merelyexamples and are not intended to be limiting. For example, the formationof a first feature over a second feature in the description that followsmay include embodiments in which the first and second features areformed in direct contact, and may also include embodiments in whichadditional features may be formed and/or disposed between the first andsecond features, such that the first and second features may not be indirect contact. In addition, the present disclosure may repeat referencenumerals and/or letters in the various examples. This does not in itselfdictate a relationship between the various embodiments and/orconfigurations discussed.

Further, spatially relative terms, such as “beneath,” “below,” “lower,”“above,” “upper” and the like, may be used herein for ease ofdescription to describe one element or feature's relationship to anotherelement(s) or feature(s) as illustrated in the figures. The spatiallyrelative terms are intended to encompass different orientations of thedevice in use or operation in addition to the orientation depicted inthe figures. The apparatus may be otherwise oriented (e.g., rotated 90degrees or at other orientations) and the spatially relative descriptorsused herein may likewise be interpreted accordingly.

Terminology

Unless defined otherwise, the technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments in accordance with thedisclosure; the methods, devices, and materials are now described. Allpatents and publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the materials andmethodologies which are reported in the publications which might be usedin connection with the present disclosure.

The acronym “FET,” as used herein, refers to a field effect transistor.An example of a type of FET is referred to as a metal oxidesemiconductor field effect transistor (MOSFET). Historically, MOSFETshave been planar structures built in and on the planar surface of asubstrate such as a semiconductor wafer. But recent advances insemiconductor manufacturing have resulted in three-dimensional,fin-based MOSFET structures.

The term “bioFET” refers to a FET that includes a layer of immobilizedcapture reagents that act as surface receptors to detect the presence ofa target analyte of biological origin. A bioFET is a field-effect sensorwith a semiconductor transducer, according to some embodiments. Oneadvantage of bioFETs is the prospect of label-free operation.Specifically, bioFETs enable the avoidance of costly and time-consuminglabeling operations such as the labeling of an analyte with, forinstance, fluorescent or radioactive probes. The analytes for detectionby a bioFET will normally be of biological origin, such as—withoutlimitation—proteins, carbohydrates, lipids, tissue fragments, orportions thereof. A BioFET can be part of a broader genus of FET sensorsthat may also detect any chemical compound (known in the art as a“ChemFET”) or any other element, including ions such as protons ormetallic ions (known in the art as an “ISFET”). This disclosure appliesto all types of FET-based sensors (“FET sensor”). One specific type ofFET sensor herein is a Dual-Gate Back Side Sensing FET Sensor.

“S/D” refers to the source/drain junctions that form two of the fourterminals of a FET.

The expression “high-k” refers to a high dielectric constant. In thefield of semiconductor device structures and manufacturing processes,high-k refers to a dielectric constant that is greater than thedielectric constant of SiO₂ (i.e., greater than 3.9).

The term “analysis” generally refers to a process or step involvingphysical, chemical, biochemical, or biological analysis that includes,but is not limited to, characterization, testing, measurement,optimization, separation, synthesis, addition, filtration, dissolution,or mixing.

The term “assay” generally refers to a process or step involving theanalysis of a chemical or a target analyte and includes, but is notlimited to, cell-based assays, biochemical assays, high-throughputassays and screening, diagnostic assays, pH determination, nucleic acidhybridization assays, polymerase activity assays, nucleic acid andprotein sequencing, immunoassays (e.g., antibody-antigen binding assays,enzyme-linked immunosorbent assays (ELISAs), and immunoquantitativepolymerase chain reaction (iqPCR)), bisulfate methylation assays fordetecting methylation pattern of genes, protein assays, protein bindingassays (e.g., protein-protein, protein-nucleic acid, and protein-ligandbinding assays), enzymatic assays, coupled enzymatic assays, kineticmeasurements (e.g., kinetics of protein folding and enzymatic reactionkinetics), enzyme inhibitor and activator screening, chemiluminescenceand electrochemiluminescence assays, fluorescent assays, fluorescencepolarization and anisotropy assays, absorbance and colorimetric assays(e.g., Bradford assay, Lowry assay, Hartree-Lowry assay, Biuret assay,and bicinchoninic acid (BCA) assay), chemical assays (e.g., for thedetection of environmental pollutants and contaminants, nanoparticles,or polymers), and drug discovery assays. The apparatus, systems, andmethods described herein may use or adopt one or more of these assays tobe used with the FET sensor designs described herein.

The term “liquid biopsy” generally refers to a biopsy sample obtainedfrom a subject's bodily fluid as compared to a subject's tissue sample.The ability to perform assays using a body fluid sample is oftentimesmore desirable than using a tissue sample. The less invasive approachusing a body fluid sample has wide ranging implications in terms ofpatient welfare, the ability to conduct longitudinal disease monitoring,and the ability to obtain expression profiles even when tissue cells arenot easily accessible, for example, in the prostate gland. Assays usedto detect target analytes in liquid biopsy samples include, but are notlimited to, those described above. As a non-limiting example, acirculating tumor cell (CTC) assay can be conducted on a liquid biopsysample.

For example, a capture reagent (e.g., an antibody) immobilized on a FETsensor may be used for detection of a target analyte (e.g., a tumor cellmarker) in a liquid biopsy sample using a CTC assay. CTCs are cells thathave shed into the vasculature from a tumor and circulate, for example,in the bloodstream. Generally, CTCs are present in circulation inextremely low concentrations. To assay the CTCs, CTCs are enriched frompatient blood or plasma by various techniques known in the art. CTCs maybe stained for specific markers using methods known in the artincluding, but not limited to, cytometry (e.g., flow cytometry)-basedmethods and immunohistochemistry (IHC)-based methods. For the apparatus,systems, and methods described herein, CTCs may be captured or detectedusing a capture reagent. In another example, the nucleic acids,proteins, or other cellular milieu from the CTCs may be targeted astarget analytes for binding to, or detection by, a capture reagent.

An increase in target analyte expressing or containing CTCs may helpidentify the subject as having a cancer that is likely to respond to aspecific therapy (e.g., one associated with the target analyte) or allowfor optimization of a therapeutic regimen with, for example, an antibodyto the target analyte. CTC measurement and quantitation can provideinformation on, for example, the stage of tumor, response to therapy,disease progression, or a combination thereof. The information obtainedfrom detecting the target analyte on the CTC can be used, for example,as a prognostic, predictive, or pharmacodynamic biomarker. In addition,CTCs assays for a liquid biopsy sample may be used either alone or incombination with additional tumor marker analysis of solid biopsysamples.

The term “identification” generally refers to the process of determiningthe identity of a target analyte based on its binding to a capturereagent whose identity is known.

The term “measurement” generally refers to the process of determiningthe amount, quantity, quality, or property of a target analyte based onits binding to a capture reagent.

The term “quantitation” generally refers to the process of determiningthe quantity or concentration of a target analyte based on its bindingto a capture reagent.

The term “detection” generally refers to the process of determining thepresence or absence of a target analyte based on its binding to acapture reagent. Detection includes, but is not limited to,identification, measurement, and quantitation.

The term “chemical” refers to a substance, compound, mixture, solution,emulsion, dispersion, molecule, ion, dimer, macromolecule such as apolymer or protein, biomolecule, precipitate, crystal, chemical moietyor group, particle, nanoparticle, reagent, reaction product, solvent, orfluid any one of which may exist in the solid, liquid, or gaseous state,and which is typically the subject of an analysis.

The term “reaction” refers to a physical, chemical, biochemical, orbiological transformation that involves at least one chemical and thatgenerally involves (e.g., in the case of chemical, biochemical, andbiological transformations) the breaking or formation of one or morebonds such as covalent, noncovalent, van der Waals, hydrogen, or ionicbonds. The term “reaction” includes chemical reactions such as synthesisreactions, neutralization reactions, decomposition reactions,displacement reactions, reduction-oxidation reactions, precipitation,crystallization, combustion reactions, and polymerization reactions, aswell as covalent and noncovalent binding, phase change, color change,phase formation, crystallization, dissolution, light emission, changesof light absorption or emissive properties, temperature change or heatabsorption or emission, conformational change, and folding or unfoldingof a macromolecule such as a protein.

“Capture reagent,” as used herein, is a molecule or compound capable ofbinding the target analyte or target reagent, which can be directly orindirectly attached to a substantially solid material. The capture agentcan be a chemical, and specifically any substance for which there existsa naturally occurring target analyte (e.g., an antibody, polypeptide,DNA, RNA, cell, virus, etc.) or for which a target analyte can beprepared, and the capture reagent can bind to one or more targetanalytes in an assay.

“Target analyte,” as used herein, is the substance to be detected in thetest sample using the present disclosure. The target analyte can be achemical, and specifically any substance for which there exists anaturally occurring capture reagent (e.g., an antibody, polypeptide,DNA, RNA, cell, virus, etc.) or for which a capture reagent can beprepared, and the target analyte can bind to one or more capturereagents in an assay. “Target analyte” also includes any antigenicsubstances, antibodies, or combinations thereof. The target analyte caninclude a protein, a peptide, an amino acid, a carbohydrate, a hormone,a steroid, a vitamin, a drug including those administered fortherapeutic purposes as well as those administered for illicit purposes,a bacterium, a virus, and metabolites of or antibodies to any of theabove substances.

“Test sample,” as used herein, means the composition, solution,substance, gas, or liquid containing the target analyte to be detectedand assayed using the present disclosure. The test sample can containother components besides the target analyte, can have the physicalattributes of a liquid, or a gas, and can be of any size or volume,including for example, a moving stream of liquid or gas. The test samplecan contain any substances other than the target analyte as long as theother substances do not interfere with the binding of the target analytewith the capture reagent or the specific binding of the first bindingmember to the second binding member. Examples of test samples include,but are not limited to, naturally-occurring and non-naturally occurringsamples or combinations thereof. Naturally-occurring test samples can besynthetic or synthesized. Naturally-occurring test samples include bodyor bodily fluids isolated from anywhere in or on the body of a subject,including, but not limited to, blood, plasma, serum, urine, saliva orsputum, spinal fluid, cerebrospinal fluid, pleural fluid, nippleaspirates, lymph fluid, fluid of the respiratory, intestinal, andgenitourinary tracts, tear fluid, saliva, breast milk, fluid from thelymphatic system, semen, cerebrospinal fluid, intra-organ system fluid,ascitic fluid, tumor cyst fluid, amniotic fluid and combinationsthereof, and environmental samples such as ground water or waste water,soil extracts, air, and pesticide residues or food-related samples.

Detected substances can include, for example, nucleic acids (includingDNA and RNA), hormones, different pathogens (including a biologicalagent that causes disease or illness to its host, such as a virus (e.g.,H7N9 or HIV), a protozoan (e.g., Plasmodium-causing malaria), or abacteria (e.g., E. coli or Mycobacterium tuberculosis)), proteins,antibodies, various drugs or therapeutics or other chemical orbiological substances, including hydrogen or other ions, non-ionicmolecules or compounds, polysaccharides, small chemical compounds suchas chemical combinatorial library members, and the like. Detected ordetermined parameters may include, but are not limited to, pH changes,lactose changes, changing concentration, particles per unit time where afluid flows over the device for a period of time to detect particles(e.g., particles that are sparse), and other parameters.

As used herein, the term “immobilized,” when used with respect to, forexample, a capture reagent, includes substantially attaching the capturereagent at a molecular level to a surface. For example, a capturereagent may be immobilized to a surface of the substrate material usingadsorption techniques including non-covalent interactions (e.g.,electrostatic forces, van der Waals, and dehydration of hydrophobicinterfaces) and covalent binding techniques where functional groups orlinkers facilitate attaching the capture reagent to the surface.Immobilizing a capture reagent to a surface of a substrate material maybe based on the properties of the substrate surface, the medium carryingthe capture reagent, and the properties of the capture reagent. In somecases, a substrate surface may be first modified to have functionalgroups bound to the surface. The functional groups may then bind tobiomolecules or biological or chemical substances to immobilize themthereon.

The term “nucleic acid” generally refers to a set of nucleotidesconnected to each other via phosphodiester bond and refers to anaturally occurring nucleic acid to which a naturally occurringnucleotide existing in nature is connected, such as DNA that includesdeoxyribonucleotides having any of adenine, guanine, cytosine, andthymine connected to each other and/or RNA that includes ribonucleotideshaving any of adenine, guanine, cytosine, and uracil connected to eachother. In addition, non-naturally occurring nucleotides andnon-naturally occurring nucleic acids are within the scope of thenucleic acid of the present disclosure. Examples include peptide nucleicacids (PNA), peptide nucleic acids with phosphate groups (PHONA),bridged nucleic acids/locked nucleic acids (BNA/LNA), and morpholinonucleic acids. Further examples include chemically-modified nucleicacids and nucleic acid analogues, such as methylphosphonate DNA/RNA,phosphorothioate DNA/RNA, phosphoramidate DNA/RNA, and 2′-O-methylDNA/RNA. Nucleic acids include those that may be modified. For example,a phosphoric acid group, a sugar, and/or a base in a nucleic acid may belabeled as necessary. Any substance for nucleic acid labeling known inthe art can be used for labeling. Examples thereof include, but are notlimited to, radioactive isotopes (e.g., 32P, 3H, and 14C), DIG, biotin,fluorescent dyes (e.g., FITC, Texas, cy3, cy5, cy7, FAM, HEX, VIC, JOE,Rox, TET, Bodipy493, NBD, and TAMRA), and luminescent substances (e.g.,acridinium ester).

The term “aptamer,” as used herein, refers to oligonucleic acids orpeptide molecules that bind to a specific target molecule. The conceptof using single-stranded nucleic acids (aptamers) as affinity moleculesfor protein binding is based on the ability of short sequences to fold,in the presence of a target, into unique, three-dimensional structuresthat bind the target with high affinity and specificity. Aptamers can beoligonucleotide ligands selected for high-affinity binding to moleculartargets.

The term “antibody” as used herein refers to a polypeptide of theimmunoglobulin family that is capable of binding a corresponding antigennon-covalently, reversibly, and in a specific manner. For example, anaturally occurring IgG antibody is a tetramer that includes at leasttwo heavy (H) chains and two light (L) chains inter-connected bydisulfide bonds. Each heavy chain includes a heavy chain variable region(abbreviated herein as “VH”) and a heavy chain constant region. Theheavy chain constant region includes three domains: CH1, CH2, and CH3.Each light chain includes a light chain variable region (abbreviatedherein as “VL”) and a light chain constant region. The light chainconstant region includes one domain, CL. The VH and VL regions can befurther subdivided into regions of hypervariability, termedcomplementarity determining regions (CDR), interspersed with regionsthat are more conserved, termed framework regions (FR). Each VH and VLis composed of three CDRs and four FRs arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, and FR4. The three CDRs constitute about 15-20% of the variabledomains. The variable regions of the heavy and light chains contain abinding domain that interacts with an antigen. The constant regions ofthe antibodies may mediate the binding of the immunoglobulin to hosttissues or factors, including various cells of the immune system (e.g.,effector cells) and the first component (C1q) of the classicalcomplement system.

The term “antibody” includes, but is not limited to, monoclonalantibodies, human antibodies, humanized antibodies, chimeric antibodies,and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Idantibodies to antibodies of the present disclosure). The antibodies canbe of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), orsubclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2).

The term “polymer” means any substance or compound that is composed oftwo or more building blocks (‘mers’) that are repetitively linked toeach other. For example, a “dimer” is a compound in which two buildingblocks have been joined together. Polymers include both condensation andaddition polymers. Examples of condensation polymers include polyamide,polyester, protein, wool, silk, polyurethane, cellulose, andpolysiloxane. Examples of addition polymers are polyethylene,polyisobutylene, polyacrylonitrile, poly(vinyl chloride), andpolystyrene. Other examples include polymers having enhanced electricalor optical properties (e.g., a nonlinear optical property) such aselectroconductive or photorefractive polymers. Polymers include bothlinear and branched polymers.

Overview of Exemplary Biosensing Device

FIG. 1 illustrates an overview of components that may be included in abiosensor system 100. Biosensor system 100 includes a sensor array 102having at least one sensing element for detecting a biological orchemical analyte and a fluid delivery system 104 designed to deliver oneor more fluid samples to sensor array 102. Fluid delivery system 104 maybe a microfluidic well positioned above sensor array 102 to contain afluid over sensor array 102. Fluid delivery system 104 may also includemicrofluidic channels for delivering various fluids to sensor array 102.Fluid delivery system 104 may include any number of valves, pumps,chambers, channels designed to deliver fluid to sensor array 102.

A readout circuit 106 is provided to measure signals from the sensors insensor array 102 and to generate a quantifiable sensor signal indicativeof the amount of a certain analyte that is present in a target solution,according to some embodiments. Different embodiments of readout circuit106 described herein utilize digital components to reduce powerconsumption and die area.

A controller 108 may be used to send and receive electrical signals toboth sensor array 102 and readout circuit 106 to perform bio- orchemical-sensing measurements. Controller 108 may also be used to sendelectrical signals to fluid delivery system 104 to, for example, actuateone or more valves, pumps, or motors.

Sensor array 102 may include an array of bioFETs, where one or more ofthe bioFETs in the array are functionalized to detect a particulartarget analyte. Different ones of the sensors may be functionalizedusing different capture reagents for detecting different targetanalytes. Further details regarding an example design of particularbioFETs are provided below. The bioFETs may be arranged in a pluralityof rows and columns, forming a 2-dimensional array of sensors. In someembodiments, each row of bioFETs is functionalized using a differentcapture reagent. In some embodiments, each column of bioFETs isfunctionalized using a different capture reagent.

Controller 108 may include one or more processing devices, such as amicroprocessor, and may be programmable to control the operation ofreadout circuit 106 and/or sensor array 102. The details of controller108 itself are not important for the understanding of the embodimentsdescribed herein. However, the various electrical signals that may besent and received from sensor array 102 will be discussed in more detailbelow.

Dual Gate Back-Side FET Sensors

Embodiments of the present application involve various layouts of bioFETsensors in sensor array 102 that allow for an opening to expose thechannel regions of more than one bioFET sensor. Prior designs usedseparate openings over each bioFET sensor, which lead to somedisadvantages as explained in more detail herein. This particularsection describes an example bioFET sensor design that may be used inthe embodiments of the present application.

One example type of bioFET sensor that may be used in sensor array 102is the dual gate back-side FET sensor. Dual gate back-side FET sensorsutilize semiconductor manufacturing techniques and biological capturereagents to form arrayed sensors. While MOSFETs can have a single gateelectrode connected to a single electrical node, the dual gate back-sidesensing FET sensor has two gate electrodes, each of which is connectedto a different electrical node. A first one of the two gate electrodesis referred to herein as a “front-side gate,” and the second one of thetwo gate electrodes is referred to herein as a “back-side gate.” Boththe front-side gate and the back-side gate are configured such that, inoperation, each one may be electrically charged and/or discharged andthereby each influences the electric field between the source/drainterminals of the dual gate back-side sensing FET sensor. The front-sidegate is electrically conductive, separated from a channel region by afront-side gate dielectric, and configured to be charged and dischargedby an electrical circuit to which it is coupled. The back-side gate isseparated from the channel region by a back-side gate dielectric andincludes a bio-functionalized sensing layer disposed on the back-sidegate dielectric. The amount of electric charge on the back-side gate isa function of whether a bio-recognition reaction has occurred. In theoperation of dual gate back-side sensing FET sensors, the front-sidegate is charged to a voltage within a predetermined range of voltages.The voltage on the front-side gate determines a correspondingconductivity of the FET sensor's channel region. A relatively smallamount of change to the electric charge on the back-side gate changesthe conductivity of the channel region. It is this change inconductivity that indicates a bio-recognition reaction.

One advantage of FET sensors is the prospect of label-free operation.Specifically, FET sensors enable the avoidance of costly andtime-consuming labeling operations such as the labeling of an analytewith, for instance, fluorescent or radioactive probes.

FIG. 2 illustrates an exemplary dual gate back-side sensing FET sensor200, according to some embodiments. Dual gate back-side sensing FETsensor 200 includes a control gate 202 formed on a surface of substrate214 and separated therefrom by an intervening dielectric 215 disposed onsubstrate 214. An interconnect region 211 including a plurality ofinterconnect layers may be provided over one side of substrate 214.Substrate 214 includes a source region 204, a drain region 206, and achannel region 208 between source region 204 and drain region 206. Insome embodiments, substrate 214 has a thickness between about 100 nm andabout 130 nm. Gate 202, source region 204, drain region 206, and channelregion 208 may be formed using suitable CMOS process technology. Gate202, source region 204, drain region 206, and channel region 208 form aFET. An isolation layer 210 is disposed on the opposing side ofsubstrate 214 from gate 202. In some embodiments, isolation layer 210has a thickness of about 1 μm. In this disclosure the side of substrate214 over which gate 202 is disposed is referred to as the “front-side”of substrate 214. Similarly, the side of substrate 214 on whichisolation layer 210 is disposed is referred to as the “back-side.”

An opening 212 is provided in isolation layer 210. Opening 212 may besubstantially aligned with gate 202. In some embodiments, opening 212 islarger than gate 202 and may extend over multiple dual gate back-sidesensing FET sensors. An interface layer (not shown) may be disposed inopening 212 on the surface of channel region 208. The interface layermay be operable to provide an interface for positioning and immobilizingone or more receptors for detection of biomolecules or bio-entities.Further details regarding the interface layer are provided herein.

Dual gate back-side sensing FET sensor 200 includes electrical contacts216 and 218 to drain region 206 and source region 204, respectively. Afront-side gate contact 220 may be made to gate 202, while a back-sidegate contact 222 may be made to channel region 208. It should be notedthat back-side gate contact 222 does not need to physically contactsubstrate 214 or any interface layer over substrate 214. Thus, while aFET can use a gate contact to control conductance of the semiconductorbetween the source and drain (e.g., the channel), dual gate back-sidesensing FET sensor 200 allows receptors formed on a side opposing gate202 of the FET device to control the conductance, while gate 202provides another region to control the conductance. Therefore, dual gateback-side sensing FET sensor 200 may be used to detect one or morespecific biomolecules or bio-entities in the environment around and/orin opening 212, as discussed in more detail using various examplesherein.

Dual gate back-side sensing FET sensor 200 may be connected to:additional passive components such as resistors, capacitors, inductors,and/or fuses; other active components, including p-channel field effecttransistors (PFETs), n-channel field effect transistors (NFETs),metal-oxide-semiconductor field effect transistors (MOSFETs), highvoltage transistors, and/or high frequency transistors; other suitablecomponents; or combinations thereof. It is further understood thatadditional features can be added in dual gate back-side sensing FETsensor 200, and some of the features described can be replaced oreliminated, for additional embodiments of dual gate back-side sensingFET sensor 200.

FIG. 3 illustrates a schematic of a portion of an exemplary addressablearray 300 of bioFET sensors 304 connected to bit lines 306 and wordlines 308. It is noted that the terms bit lines and word lines are usedherein to indicate similarities to array construction in memory devices,however, there is no implication that memory devices or a storage arraynecessarily be included in the array. Addressable array 300 may havesimilarities to that employed in other semiconductor devices such asdynamic random access memory (DRAM) arrays. For example, dual gateback-side sensing FET sensor 200, described above with reference to FIG.2 , may be formed in a position that a capacitor would be found in aDRAM array. Schematic 300 is exemplary only and one would recognizeother configurations are possible.

BioFET sensors 304 may each be substantially similar to dual gateback-side sensing FET sensor 200 according to some embodiments. FETs 302are configured to provide an electrical connection between a drainterminal of bioFET sensor 304 and bit line 306. In this way, FETs 302are analogous to access transistors in a DRAM array. In someembodiments, bioFET sensors 304 are dual gate back-side sensing FETsensors and each include a sensing gate provided by a receptor materialdisposed on a dielectric layer overlying a FET channel region disposedat a reaction site, and a control gate provided by a gate electrode(e.g., polysilicon) disposed on a dielectric layer overlying the FETchannel region.

Addressable array 300 shows an array formation designed to detect smallsignal changes provided by biomolecules or bio-entities introduced tobioFET sensors 304. The arrayed format using bit lines 306 and wordlines 308 allows for a smaller number of input/output pads since commonterminals of different FETs in the same row or column are tied together.Amplifiers may be used to enhance the signal strength to improve thedetection ability of the device having the circuit arrangement ofschematic 300. In some embodiments, when voltage is applied toparticular word lines 308 and bit lines 306, the corresponding accesstransistors 302 will be turned ON (e.g., like a switch). When the gateof the associated bioFET sensor 304 (e.g., such as back-side gate 222 ofthe dual gate back-side sensing FET sensor 200) has its charge affectedby the bio-molecule presence, a threshold voltage of bioFET sensor 304is changed, thereby modulating the current (e.g., I_(ds)) for a givenvoltage applied to back-side gate 222. The change of the current (e.g.,I_(ds)) or threshold voltage (V_(t)) can serve to indicate detection ofthe relevant biomolecules or bio-entities.

Referring to FIG. 4 , an exemplary schematic 400 is presented. Exemplaryschematic 400 includes access transistor 302 and bioFET sensor 304arranged as an array 401 of individually addressable pixels 402. Array401 may include any number of pixels 402. For example, array 401 mayinclude 128×128 pixels. Other arrangements may include 256×256 pixels ornon-square arrays such as 128×256 pixels.

Each pixel 402 includes access transistor 302 and bioFET sensor 304along with other components that may include one or more heaters 408 anda temperature sensor 410. In this example, access transistor 302 is ann-channel FET. An n-channel FET 412 may also act as an access transistorfor temperature sensor 410. In some embodiments, the gates of FETs 302and 412 are connected, though this is not required. Each pixel 402 (andits associated components) may be individually addressed using columndecoder 404 and row decoder 406. In some embodiments, each pixel 402 hasa size of about 10 micrometers by about 10 micrometers. In someembodiments, each pixel 402 has a size of about 5 micrometers by about 5micrometers or has a size of about 2 micrometers by about 2 micrometers.

Column decoder 406 and row decoder 404 may be used to control the ON/OFFstate of both n-channel FETs 302 and 412 (e.g., voltage is applied tothe gates of FETs 302 and 412 together, and voltage is applied to thedrain regions of FETs 302 and 412 together). Turning ON n-channel FET302 provides a voltage to an S/D region of bioFET sensor 304. WhenbioFET sensor 304 is ON, a current I_(ds) flows through bioFET sensor304 and may be measured.

Heater 408 may be used to locally increase a temperature around bioFETsensor 304. Heater 408 may be constructed using any known technique,such as forming a metal pattern with a high current running through it.Heater 408 may also be a thermoelectric heater/cooler, like a Peltierdevice. Heater 408 may be used during certain biological tests such asto denature DNA or RNA or to provide a binding environment for certainbiomolecules. Temperature sensor 410 may be used to measure the localtemperature around bioFET sensor 304. In some embodiments, a controlloop may be created to control the temperature using heater 408 and thefeedback received from temperature sensor 410. In some embodiments,heater 408 may be a thermoelectric heater/cooler that allows for localactive cooling of the components within pixel 402.

Referring to FIG. 5A, a cross section of a semiconductor device 500having a dual gate back-side sensing FET sensor 502 and an accesstransistor 522 is provided, according to some embodiments. Dual gateback-side sensing FET sensor 502 includes gate 506, S/D regions 510 oneither side of gate 506, and a channel region 508 between S/D regions510 formed within a substrate 504. A gate dielectric layer also existsbetween gate 506 and channel region 508, but is not shown in the figure.For convenience in describing certain elements, substrate 504 isillustrated as having a front surface 505 and an opposite, parallel backsurface 507. It should be noted that the various components of FIG. 5Aare not intended to be drawn to scale and are exaggerated for visualconvenience, as would be understood by a person skilled in the relevantart.

Dual gate back-side sensing FET sensor 502 includes an interface layer516 deposited over an isolation layer 512 and within an opening 514 overchannel region 508. In some embodiments, interface layer 516 has athickness between about 20 Å and about 40 Å. Interface layer 516 may bea high-K dielectric material such as, for example, hafnium silicate,hafnium oxide, zirconium oxide, aluminum oxide, tantalum pentoxide,hafnium dioxide-alumina (HfO₂—Al₂O₃) alloy, or any combinations thereof.Interface layer 516 may act as a support for the attachment of capturereagents as will be discussed in more detail below in the sectiondirected to biological sensing. A solution containing capture reagents,target reagents, wash solution, or any other biological or chemicalspecies may be provided within opening 514 over channel region 508.Further details regarding the fabrication process of dual gate back-sidesensing FET sensor 502 may be found in co-owned U.S. Pat. No. 9,080,969,the disclosure of which is incorporated by reference herein.

Access transistor 522 may be coupled to dual gate back-side sensing FETsensor 502 in an arrangement such as that illustrated in FIG. 3 withaccess transistor 302 and FET sensor 304, according to some embodiments.Access transistor 522 similarly includes a gate 524, S/D regions 528 oneither side of gate 524, and a channel region 526 between S/D regions528 formed within substrate 504. Access transistor 522 includesisolation layer 512 over its channel region 526 (i.e., no opening isformed through isolation layer 512 over channel region 526.) As shown inFIG. 5 , interface layer 516 may still be deposited on isolation layer512 over access transistor 522. Access transistor 522 may be separatedfrom dual gate back-side sensing FET sensor 502 using shallow trenchisolation (STI) 530 as would be understood by a person skilled in therelevant art.

In some embodiments, gate 506, gate 524, S/D regions 510, and S/Dregions 528 are coupled to various layers of metal interconnects withininterconnect region 518. The metal interconnects may be used to makeelectrical connection with various doped regions and other devicesformed within substrate 508. Any number of levels of metalinterconnects, along with metal plugs connecting between levels, may beused in interconnect region 518. The process of forming such metalinterconnects would be understood by a person skilled in the relevantart.

Semiconductor device 500 may also include a carrier substrate 520coupled to interconnect region 518, according to some embodiments.Carrier substrate 520 may include one or more conductive portions tomake electrical connection with certain metal interconnects ofinterconnect region 518. Carrier substrate 520 may be used to providephysical support and stability to the thin layers that make up substrate504 and interconnect region 518.

Dual gate back-side FET sensor 502 may be coupled to additionalcircuitry fabricated within substrate 504. The additional circuitry mayinclude MOSFET devices, resistors, capacitors, and/or inductors to formcircuitry to aid in the operation of dual gate back-side sensing FETsensor 502. The circuitry may represent a readout circuit used tomeasure a signal from dual gate back-side FET sensor 502 that isindicative of analyte detection. The circuitry may include amplifiers,analog to digital converters (ADCs), digital to analog converters(DACs), voltage generators, logic circuitry, and/or DRAM memory, to namea few examples. All or some of the components of the additionalcircuitry may be integrated in substrate 504. It should be understoodthat many bioFET sensors, each substantially similar to dual gateback-side FET sensor 502, may be integrated in substrate 504 and coupledto the additional circuitry. In another example, all or some of thecomponents of the additional circuitry are provided on anothersemiconductor substrate separate from substrate 504. In yet anotherexample, some components of the additional circuitry are integrated insubstrate 504, and some components of the additional circuitry areprovided on another semiconductor substrate.

FIG. 5B illustrates a semiconductor device 500 with a fluid 532 disposedover the FETs. Fluid 532 may include an ion concentration 534 that isgenerated due to, for example, a change in pH of fluid 532, enzymaticreactions between target analytes and capture reagents, bindingreactions between target analytes and capture reagents, or otherbiological interactions. A fluid gate 536 may be provided to form thebackside gate of dual gate back-side FET sensor 502. The presence of ionconcentration 534 near channel region 508 affects the operation ofbackside gate of dual gate back-side FET sensor 502 and can be detectedas a change in the drain current I_(ds) for a given potential applied toeither gate 506 or fluid gate 536. Some example detection studies usingdual gate back-side FET sensor 502 are discussed in more detail below.

Fluid 532 may be provided into opening 514 by flowing through amicrofluidic channel disposed over back surface 507, according to someembodiments. The microfluidic channel may be bonded directly to eitherinterface layer 516 or isolation layer 512. The microfluidic channel maybe molded from a polymer material such as polydimethylsiloxane (PDMS) orpolyethylene glycal (PEG). In some embodiments, fluid 532 is disposed ina microfluidic well that quiescently holds fluid 532 and allows fluid532 to enter through opening 514.

FIG. 6A illustrates an example layout of dual gate back-side FET sensor502 and access transistor 522, according to some embodiments. Similarelements to those illustrated in FIG. 5 are identified with the samelabels in FIG. 6A. Opening 514 is illustrated as being slightly widerthan gate 506 in order to be seen in the top-down view. The exact sizeof opening 514 may vary within the bounds of S/D regions 510. However,in this device, opening 510 only exposes the channel region (alignedwith gate 506) of a single dual gate back-side FET sensor 502. Metallayers 602 are used to make electrical contact through contacts 604 toS/D regions 510 of dual gate back-side FET sensor 502 and S/D regions528 of access transistor 522. Metal layers 602 and contacts 604 may beprovided within interconnect region 518 in FIG. 5 .

FIG. 6B illustrates an example circuit representation of dual gateback-side FET sensor 502 and access transistor 522 that corresponds withthe layout illustrated in FIG. 6A, according to some embodiments. Avoltage (vpg) may be applied to gate 506 of dual gate back-side FETsensor 502 to bias the sensor (e.g., to an ON state) during a sensingoperation. To measure a current from dual gate back-side FET sensor 502,a voltage (sel) may be applied to gate 524 of access transistor 522. Ifvoltage is also applied to terminal n2, then a current may flow throughboth dual gate back-side FET sensor 502 and access transistor 522. Amagnitude of the current may be affected by any target analytes detectedby dual gate back-side FET sensor 502 as will be described in moredetail below.

Opening 514 as illustrated in both FIG. 5A and FIG. 6A has a width thatis on the order of the gate length of dual gate back-side FET sensor502, according to some embodiments. Opening 514 is typically constrainedto only exposing channel region 508 of dual gate back-side FET sensor502 to avoid having fluid 532 affect the operation of other FETs insubstrate 504 (such as access transistor 522.) It can be difficult forfluid 532 to enter opening 514 due to surface tension forces andhydrophobicity of interface layer 516. These factors contribute topreventing fluid 532 from wetting the surface of interface layer 516directly above channel region 508. Due to the illustrated layout ofsemiconductor device 500 (with dual gate back-side FET sensor 502 andaccess transistor 522 substantially side-by-side), extension of opening514 may also expose channel region 526 of access transistor 522, whichaffects the operation of access transistor 522.

According to some embodiments, a plurality of dual gate back-side FETsensors are arranged side-by-side in a row to allow for an extendedopening to span across each of the dual gate back-side FET sensors. FIG.7A illustrates an example layout 700 of a plurality of pixels 702-1through 702-N arranged in a single row with each pixel having a dualgate back-side FET sensor 704 and an access transistor 706, according tosome embodiments. It should be understood that any following descriptionof a single pixel equally pertains to all other pixels in the array.Furthermore, although only a single row of pixels is illustrated, itshould be understood that many rows of pixels may be used to provide a2-dimensional matrix of pixels, each containing a dual gate back-sideFET sensor and a corresponding access transistor. Using a pixel layoutsuch as the one illustrated in FIG. 7A vs. the pixel layout illustratedin FIG. 6A results in about a 20% reduction in the device footprint ofthe sensor array.

Layout 700 includes an opening 708 to expose the channel regions of eachdual gate back-side FET sensor 704, according to some embodiments. Sinceeach of the dual gate back-side FET sensors across the row of pixels arearranged side-by-side, opening 708 may span across the entire row ofpixels (e.g., in the X-direction.)

As shown in pixel 702-N, each dual gate back-side FET sensor 704 mayhave a gate structure 710 that includes two gates over two channelregions with S/D regions 712 a, 712 b, and 712 c arranged between thetwo gates, according to some embodiments. S/D region 712 b may beelectrically connected with S/D region 716 of access transistor 706using metal interconnect 714. This design of dual gate back-side FETsensor 704 with two gates effectively doubles the current output of eachdual gate back-side FET sensor 704 by flowing a first current from 712 bto 712 a and a second current from 712 b to 712 c when dual gateback-side FET sensor 704 is biased ON. S/D regions 712 a and 712 c maybe grounded. According to an embodiment, each dual gate back-side FETsensor 704 has its S/D regions 712 a and 712 c. S/D regions 712 a and712 c may represent the source terminal of each dual gate back-side FETsensor 704 when each dual gate back-side FET sensor 704 is an n-channeldevice. S/D regions 712 a and 712 c may represent the drain terminal ofeach dual gate back-side FET sensor 704 when each dual gate back-sideFET sensor 704 is a p-channel device. Due to the side-by-side layout ofeach dual gate back-side FET sensor 704, adjacent FET sensors may sharethe same S/D region 712 a and 712 c.

It should be understood that using a two-gate design in each pixel asillustrated in FIG. 7A is only one example, and that a single-gatedesign may be used as well in one or more or all of the pixels. Anexample of the single-gate design is illustrated in the layout diagramof dual gate back-side FET sensor 502 in FIG. 6A. By sharing S/D regions712 a and 712 c across adjacent pixels, the overall size of the sensingarray may be reduced by eliminating dead space between adjacent pixels.

According to some embodiments, gate structure 710 of each dual gateback-side FET sensor 704 across pixels 702-1 to 702-N are coupledtogether. In this way, each dual gate back-side FET sensor 704 may bebiased ON at the same time, and choosing which sensor to measure from isperformed via an applied voltage to gate 718 of a specific accesstransistor 706. S/D region 720 of each access transistor 706 may beelectrically coupled to a voltage source through metal interconnect 722.According to an embodiment, the S/D regions 720 of each accesstransistor 706 are electrically coupled together, such that only voltageapplied to gate 718 determines which access transistor 706 is biased ON.Furthermore, current from a corresponding dual gate back-side FET sensor704 may be measured from any node electrically connected to metalinterconnect 722.

FIG. 7B illustrates a cross-section view taken across a row of dual gateback-side FET sensors 704 between pixels 702-1 and 702-N, according tosome embodiments. Opening 708 stretches across multiple bioFET sensorsin the X-direction to expose a portion of back surface 507 of substrate504. The exposed portion of back surface 507 includes the surfaces of aplurality of channel regions 508 spanning across more than one dual gateback-side FET sensor. Front surface 505 of substrate 504 includes aplurality of gates 710 patterned over channel regions 508.

Interface layer 516 is disposed within opening 708 to provide a surfacefor binding various capture reagents, according to some embodiments. Dueto the larger width of opening 708, a fluid carrying either the capturereagents or target analytes that interact with the capture reagents haveeasier access to interface layer 516 directly on back surface 507.

The fluid may be provided into opening 708 by flowing the fluid througha microfluidic channel disposed over back surface 507, according to someembodiments. The microfluidic channel may be bonded directly to eitherinterface layer 516 or isolation layer 512. The microfluidic channel maybe molded from a polymer material such as, for example,polydimethylsiloxane (PDMS) or polyethylene glycal (PEG). Themicrofluidic channel may run along the X direction such that fluid flowsin the X-direction across opening 708. In some embodiments, a differentmicrofluidic channel is provided for each row of dual gate back-side FETsensors 704 in a two-dimensional sensing array. In other embodiments, amicrofluidic channel includes a width that is wide enough to encompassmore than one, or all, rows of dual gate back-side FET sensors 704 inthe two-dimensional sensing array.

In some embodiments, the fluid is disposed in a microfluidic well thatquiescently holds the fluid and allows the fluid to enter throughopening 708. According to some embodiments, the microfluidic well holdsbetween about 1 μL and about 100 μL of fluid. The microfluidic well maybe sized and positioned such that only a portion of the total number ofdual gate back-side FET sensors 704 in a two-dimensional sensing arrayare exposed to the fluid within the well. In another example, all of thedual gate back-side FET sensors 704 in a two-dimensional sensing arrayare exposed to the fluid within the well.

FIG. 7C illustrates a circuit representation of layout 700, according tosome embodiments. The row of pixels 702-1 through 702-N are shown witheach access transistor 706 having its drain terminal (in the case of ann-channel device) connected together for measuring a current I_(out)from the selected dual gate back-side FET sensor 704.

Opening 708 may stretch across the entire extent of a given row ofpixels 702-1 to 702-N, or may stretch across a subset of the pixels702-1 to 702-N. The total number of pixels (N) in a row may be as few as2 and as many as 4096. Additionally, opening 708 is not limited to onlystretching across one row of pixels. In some embodiments, opening 708also extends in the Y-direction to expose the channel regions of dualgate back-side FET sensors in other rows. When providing an opening thatextends in both X and Y directions to expose the channel regions ofmultiple dual gate back-side FET sensors in a two-dimensional array,each of the access transistors 706 may be located outside of thetwo-dimensional array of dual gate back-side FET sensors.

FIG. 8A illustrates another layout 800 of dual gate back-side FETsensors BF₁-BF_(N), according to some embodiments. In layout 800, dualgate back-side FET sensors BF₁-BF_(N) are again arranged in a same rowside-by-side such that an opening 708 spans across multiple sensors toexpose channel regions of each dual gate back-side FET sensorBF₁-BF_(N). However, unlike layout 700, each dual gate back-side FETsensor is electrically coupled with two other FET devices. In theillustrated example, dual gate back-side FET sensor BF₁ is coupled withaccess transistor S₁A and shunt transistor S₁B while dual gate back-sideFET sensor BF₂ is coupled with access transistor S₂A and shunttransistor S₂B. This same arrangement may be repeated for each pixel inthe row.

It should be understood that using a two-gate design for each dual gateback-side FET sensor BF₁-BF_(N) as illustrated in FIG. 8A is only oneexample, and that a single-gate design may be used as well. An exampleof the single-gate design is illustrated in the layout diagram of dualgate back-side FET sensor 502 in FIG. 6A. Also by sharing grounded S/Dregions between adjacent sensors, the overall size of the sensing arraymay be reduced by eliminating dead space between adjacent sensors.

FIG. 8B illustrates a circuit representation of layout 800 with the samelabels used from FIG. 8A to identify the same elements, according tosome embodiments. An example operation will now be provided to describethe function of the shunt transistor. When a current is desired to bemeasured from dual gate back-side FET sensor BF₁, a voltage is appliedto the gate of access transistor S₁A to bias the transistor ON, thuscreating a conductive path to BF₁, and current Iout can be measured.When access transistor S₁A is biased ON, shunt transistor S₁B is biasedto be off to cut off the shunted path to ground. According to anembodiment, an inverter is used to ensure that the signal received atthe gate of access transistor S₁A is inverted compared to the signalreceived at the gate of shunt transistor S₁B. The inverter may bearranged in each pixel to ensure correct operation of each accesstransistor S₁A and shunt transistor SIB. The inventor may also becoupled with a NAND gate having inputs from corresponding bit and wordlines for the given pixel.

Because current from only dual gate back-side FET sensor BF₁ is desired,access transistor S₂A is biased to be off. Shunt transistor 52B isbiased to be ON to ensure that no voltage is applied to the unselecteddual gate back-side FET sensor BF₂. If shunt transistor 52B were notused, a floating (e.g., unknown) voltage potential may exist and causeunwanted current flow through BF₂. The same description appliesvisa-versa when current is desired to be measured from BF₂.

FIG. 9 illustrates an example method 900 for fabricating a plurality ofdual gate back-side FET sensors such as those illustrated in layouts 700and 800, according to some embodiments. Method 900 may include formingthe dual gate back-side FET sensors using one or more process stepscompatible with or typical to a complementary metal-oxide-semiconductor(CMOS) process. It is understood that additional operations can beprovided before, during, and after method 900, and some of the stepsdescribed below can be replaced or eliminated, for additionalembodiments of the method. Further, it is understood that method 900includes operations having features of a typical CMOS technology processflow and thus, are only described briefly herein. Typical CMOStechnology processes may include photolithography; ion implantation;diffusion; deposition including physical vapor deposition (PVD), metalevaporation or sputtering, chemical vapor deposition (CVD),plasma-enhanced chemical vapor deposition (PECVD), atmospheric pressurechemical vapor deposition (APCVD), low-pressure CVD (LPCVD), highdensity plasma CVD (HDPCVD), atomic layer CVD (ALCVD), spin on coating;and etching including wet etching, dry etching, and plasma etching.Reference may be made to certain elements illustrated in FIGS. 5A and7B.

Method 900 begins at block 902 where a substrate is provided. Thesubstrate may be a semiconductor substrate. The semiconductor substratemay be a silicon substrate. Alternatively, the substrate may includeanother elementary semiconductor, such as germanium; a compoundsemiconductor including silicon carbide; an alloy semiconductorincluding silicon germanium; or combinations thereof. In someembodiments, the substrate is a semiconductor on insulator (SOI)substrate. The substrate may include doped regions, such as p-wells andn-wells. In the present disclosure, a wafer is a workpiece that includesa semiconductor substrate and various features formed in and over andattached to the semiconductor substrate. The wafer may be in variousstages of fabrication and is processed using the CMOS process. After thevarious stages of fabrication are completed, the wafer is separated intoindividual dies that are packaged into an integrated chip.

Method 900 then proceeds to block 904 where a plurality of gates areformed on a front surface of the substrate. A first set of the pluralityof gates may act as gates of dual gate back-side FET sensors while asecond set of the plurality of gates may act as gates of various othertransistors in the substrate, such as access transistors and/or shunttransistors. According to some embodiments, the gates are polysilicon.Other exemplary gate materials include metals such as, copper (Cu),tungsten (W), titanium (Ti), tantalum (Ta), chromium (Cr), platinum(Pt), silver (Ag), gold (Au); suitable metallic compounds like titaniumnitride (TiN), tantalum nitride (TaN), nickel silicide (NiSi), cobaltsilicide (CoSi); combinations thereof; and/or other suitable conductivematerials.

A gate dielectric is provided between the plurality of gates and thefront surface of the substrate. In some embodiments, the gate dielectricis silicon oxide. Other exemplary gate dielectrics include siliconnitride, silicon oxynitride, a dielectric with a high dielectricconstant (high k), or combinations thereof. Examples of high k materialsinclude hafnium silicate, hafnium oxide, zirconium oxide, aluminumoxide, tantalum pentoxide, hafnium dioxide-alumina (HfO₂—Al₂O₃) alloy,or combinations thereof.

Method 900 proceeds to block 906 where S/D regions are formed in thesubstrate on either side of each of the plurality of gates. The S/Dregions may include n-type dopants or p-type dopants depending on theFET configuration (i.e., n-channel or p-channel.) S/D regions of boththe dual gate back-side FET sensors and other transistors, such asaccess transistors and/or shunt transistors, may be formed at the sametime. Additional interconnect layers may be formed to create electricalconnections to each of the plurality of gates and S/D regions, such asthose formed within interconnect region 518.

A carrier substrate 520 may also be attached to interconnect region 518to allow for various subsequent operations to the back side of thesubstrate without affecting the structural integrity of thesemiconductor substrate. In some embodiments, the carrier substrate 520is bonded to a last metal interconnect layer of interconnect region 518.In some embodiments, carrier substrate 520 is bonded to a passivationlayer formed on the interconnect region. The carrier substrate may beattached to the device substrate using fusion, diffusion, eutectic,and/or other suitable bonding methods. Exemplary compositions for thecarrier substrate include silicon, glass, and quartz. In someembodiments, the carrier substrate may include other functionality suchas interconnect features, bonding sites, defined cavities, and/or othersuitable features. The carrier substrate may be removed duringsubsequent processing (e.g., after thinning).

Method 900 proceeds to block 908 where an opening is formed through adielectric layer on the back side of the substrate, according to someembodiments. For example, an opening 708 may be etched through isolationlayer 512 to expose the back side 507 of substrate 504. According tosome embodiments, opening 708 is large enough to expose the channelregions 508 of more than one dual gate back-side FET sensor. Opening 708may span across a row of dual gate back-side FET sensors arrangedside-by-side.

The opening may be formed by first performing a dry etch such as areactive ion etch (ME) or any plasma etch to thin the dielectric layeron the back side of the substrate. Afterwards, the thin remainingportion of the dielectric layer within the opening may be removed usinga wet etch, such as a buffered oxide etch (BOE) or hydrofluoric acid(HF).

Method 900 proceeds to block 910 where an interface layer 516 isdisposed on the back surface of the substrate over the exposed channelregions within the opening, according to some embodiments. The interfacelayer is compatible for biomolecule or bio-entity binding. For example,the interface layer may provide a binding interface for biomolecules orbio-entities. The interface layer may include a dielectric material, aconductive material, and/or other suitable material for holding areceptor. Exemplary interface materials include high-k dielectric films,metals, metal oxides, dielectrics, and/or other suitable materials. As afurther example, exemplary interface layer materials include: hafniumoxide (HfO₂), tantalum oxide (Ta₂O₅), Pt, Au, W, Ti, aluminum (Al), Cu;oxides of such metals such as, for example, silicon dioxide (SiO₂),silicon nitride (Si₃N₄), aluminum oxide (Al₂O₃), titanium oxide (TiO₂),TiN, zirconium oxide (ZrO₂), tin (II) oxide (SnO), tin dioxide (SnO₂);and/or other suitable materials. The interface layer may be formed usingCMOS processes such as, for example, physical vapor deposition (PVD)(sputtering), chemical vapor deposition (CVD), plasma-enhanced chemicalvapor deposition (PECVD), atmospheric pressure chemical vapor deposition(APCVD), low-pressure CVD (LPCVD), high density plasma CVD (HDPCVD), oratomic layer CVD (ALCVD). In some embodiments, the interface layerincludes a plurality of layers.

Method 900 continues with block 912 where capture reagents are providedon the interface layer, according to some embodiments. A film treatmentor a capture reagent such as an enzyme, antibody, ligand, peptide,nucleotide, cell of an organ, organism, or piece of tissue may beprovided or bound on the interface layer for detection of a targetanalyte. For instance, to detect single-stranded deoxyribonucleic acid(ssDNA), the interface layer may be functionalized with immobilizedcomplementary ssDNA strands. Also, to detect various proteins such astumor markers, the interface layer may be functionalized with monoclonalantibodies. The capture reagents may be a part of self-assembledmonolayer (SAM) of molecules. The SAM may have head groups of silanegroups, silyl groups, silanol groups, phosphonate groups, amine groups,thiol groups, alkyl groups, alkene groups, alkyne groups, azido groups,or expoxy groups. The capture reagents are attached to the head groupsof the SAM.

In some embodiments, the same capture reagents are immobilized over alldual gate back-side FET sensors within a given opening. In this example,each of the dual gate back-side FET sensors in the opening may be biasedON when detecting a target analyte, such that the combined current fromeach dual gate back-side FET sensor is collected. Integrating thecombined signal from multiple dual gate back-side FET sensors may helpto improve either or both the signal-to-noise ratio and sensitivity ofthe sensor array with respect to the target analyte. In someembodiments, each row of dual gate back-side FET sensors in atwo-dimensional array includes the same capture reagents immobilizedover the bioFET sensors of a given row, but may include differentcapture reagents between different rows.

In some embodiments, different capture reagents are immobilized overdifferent dual gate back-side FET sensors within a given opening. Inthis example, various target analytes can be detected using the samesensing array. The current measured from a particular dual gateback-side FET sensor would be associated with a concentration of aparticular target analyte binding to the corresponding capture reagentsimmobilized over the particular dual gate back-side FET sensor.Different capture reagents may be disposed over different dual gateback-side FET sensors in the same opening using a liquid dispensingapparatus designed to carefully dispense very small amounts of liquid(e.g., less than 1 nL) in order to immobilize the capture reagents onlyover a single, or a small number of, dual gate back-side FET sensors.

Piezoelectric Mixer

As discussed above with reference to FIG. 5B, fluid may be introducedover various bioFET sensors arranged in a sensor array via one or moremicrofluidic channels. Using microfluidic channels to direct fluid flowalso provides the ability to integrate other fluidic devices such aspumps and mixers. Mixers can be especially important for enhancing theinteractions and reactions occurring between analytes in the fluid andcapture molecules on the bioFET sensors.

An integrated mixer provides mechanical force to introduce turbulenceinto the fluid. The turbulence provides a higher mixing efficiency thandiffusion or convection alone. The mixing action works to reduce theincubation time for bio-reactions to occur, such as any bindingreactions between analytes in the fluid and capture molecules on thebioFET sensors.

Mixers may be integrated anywhere along the microfluidic channel on thechip. In some embodiments, more than one mixer may be included. FIG. 10illustrates an example layout of a sensor chip 1002 that includes amicrofluidic channel 1004 having an inlet 1006 and an outlet 1008.Microfluidic channel 1004 may be patterned by molding the channel into apolymer material such as polydimethysiloxane (PDMS), or by patterningwalls that define the channel on a surface of sensor chip 1002.Microfluidic channel 1004 may have a width of less than 5 mm, less than3 mm, less than 1 mm, less than 500 μm, less than 300 μm, less than 100μm, or less than 50 μm.

Each of inlet 1006 and outlet 1008 may be formed by chemical etching,laser drilling, or mechanical drilling through a material that seals thetop of microfluidic channel 1004. The material may be a polymer such asPDMS or polyethylene glycol, or the material may be a more rigidsubstrate such as silicon or silicon dioxide (examples of silicondioxide include glass, quartz, fused silica, etc.)

According to an embodiment, microfluidic channel 1004 includes anintegrated pump 1010. Pump 1010 may be any type of well-known fluidicpump, such as a peristaltic pump, a piezoelectric pump, or anelectro-osmotic pump.

According to an embodiment, microfluidic channel 1004 includes anintegrated mixer 1012. Mixer 1012 may be a piezoelectric mixer as willbe discussed in more detail herein. Mixer 1012 may be integrated inmicrofluidic channel 1004 upstream of a sensing area 1014 where thebioFET sensor array(s) are located. As such, mixer 1012 may be providedto premix the fluid before it reaches any of the bioFET sensors.

According to an embodiment, microfluidic channel 1004 is designed todeliver fluid to sensing area 1014 having at least a first sensor 1016 aand a second sensor 1016 b. In one embodiment, each of first sensor 1016a and second sensor 1016 b includes its own integrated mixer disposednear or directly over the bioFET sensing surface. This allows for mixingto occur directly at the site where the bio-reactions occur, such as anybinding reactions between analytes in the fluid and capture molecules onthe bioFET sensors. The integrated mixers over each of sensor 1016 a andsensor 1016 b may be piezoelectric mixers.

It should be understood that sensor 1016 a may represent any number ofbioFET sensors, including any number of bioFET sensors arranged in asensing array. Thus, in an embodiment, sensor 1016 a is a first sensorarray having its own integrated mixer over the first sensing array, andsensor 1016 b is a second sensor array having its own integrated mixerover the second sensing array. In another embodiment, sensor 1016 arepresents a first group of bioFET sensors having a first common sensingwell exposing the backside of each of the bioFET sensors in the firstgroup, and sensor 1016 b represents a second group of bioFET sensorshaving a second common sensing well exposing the backside of each of thebioFET sensors in the second group. The bioFET sensors of the firstgroup and the bioFET sensors of the second group may be arranged in thesame sensor array, or may be from different sensor arrays.

An example fabrication process for a piezoelectric mixer 1100 that maybe integrated within microfluidic channel 1004 is illustrated in FIGS.11A-11E, according to an embodiment. FIG. 11A illustrates a first stagein the fabrication of mixer 1100 where a piezoelectric film stack 1101is formed on a substrate 1102. Piezoelectric film stack 1101 includes afirst electrode layer 1104, a piezoelectric film 1106, and a secondelectrode layer 1108.

Substrate 1102 may be silicon or silicon dioxide (examples of silicondioxide include glass, quartz, fused silica, etc.) In an embodimentwhere substrate 1102 is silicon, an insulating layer may first bedeposited over substrate 1102 before the formation of first electrodelayer 1104. The insulating layer may be silicon dioxide.

First electrode layer 1104 and second electrode layer 1108 can be thesame conductive material. Each of first electrode layer 1104 and secondelectrode layer 1108 may include platinum or gold, to name a fewexamples. First electrode layer 1104 and second electrode layer 1108 maybe deposited through a deposition technique such as, for example,sputtering, evaporation, or chemical vapor deposition (CVD). Firstelectrode layer 1104 and second electrode layer 1108 may each have athickness between about 50 nm and about 500 nm.

Piezoelectric film 1106 may include any material having a piezoelectricproperty. A material with a piezoelectric property exhibits a mechanicalstrain when subjected to an applied electric field. In one example, leadzirconate titanate (PZT) crystals can change a percentage of theirstatic dimension when an external electric field is applied to thematerial. PZT can be used for micro-scale applications due to itsrelative ease of depositing into a thin layer, marked demonstration ofthe piezoelectric effect, and its low cost. Other example materials thatexhibit the piezoelectric effect and could be used for piezoelectricfilm 1106 include polyvinylidene fluoride (PVDF) and lithium niobate.Piezoelectric film 1106 may be deposited using, for example, a physicalvapor deposition (PVD) or CVD technique. Piezoelectric film 1106 mayhave a thickness between about 100 nm and 5000 nm.

FIG. 11B illustrates a second stage in the fabrication process of mixer1100, according to an embodiment. A cross-section of mixer 1100illustrates a plurality of openings 1111 formed by one or more etchingprocesses to etch through a thickness of piezoelectric film stack 1101.Various mask patterns may be used to protect portions of piezoelectricfilm stack 1101 during the one or more etching processes to form adifferent mixer pattern when viewed from a top-down perspective.According to some embodiments, piezoelectric film stack 1101 may beetched using ion beam etching with argon. According to some embodiments,piezoelectric film stack 1101 may be etched using hydrochloric acid.

Three example mixer patterns (I, II, and III) are illustrated in FIG.11B, according to some embodiments. In a first pattern I, a plurality ofopenings are formed within a generally square portion of piezoelectricfilm stack 1101. In a second pattern II, a plurality of openings areformed within a generally circular portion of piezoelectric film stack1101. In a third pattern III, a serpentine opening is formed within agenerally square portion of piezoelectric film stack 1101. It should beunderstood that these patterns are provided merely as examples and arenot limiting. The openings themselves may be any shape are not limitedto being circular. Similarly, the overall shape of piezoelectric filmstack 1101 following the one or more etching processes may be any shape,and are not limited to either circular or square, when viewed from atop-down perspective.

Another etch process may be used to form recess 1110, according to anembodiment. Recess 1110 exposes first electrode layer 1104 after etchingthrough second electrode layer 1108 and piezoelectric film 1106.Electrical connection may be provided more easily to first electrodelayer 1104 due to the presence of recess 1110. Electrical connectionmust be made to each of first electrode layer 1104 and second electrodelayer 1108 in order to produce an E-field between first electrode layer1104 and second electrode layer 1108 that generates mechanical strain inpiezoelectric film 1106.

FIG. 11C illustrates a third stage in the fabrication process of mixer1100, according to an embodiment. An etching process is performed torelease a portion of piezoelectric film stack 1101 by removing a portionof substrate 1102 beneath piezoelectric film stack 1101. Substrate 1102is first protected using a photoresist or hard mask layer everywhereexcept where piezoelectric film stack 1101 is patterned over substrate1102. Then, an etching process is performed to etch away a portion ofsubstrate 1102 beneath openings 1111. Since the etch is isotropic, theetching will also continue laterally beneath openings 1111 such thatportions of substrate 1102 between openings 1111 are also removed. Theresult of the etch is illustrated as cavity 1112, according to anembodiment. The “release” etch may be performed using wet etchingtechniques or dry etching techniques. An example wet etching techniqueincludes exposing substrate 1102 to various possible concentrations ofhydrofluoric acid to form cavity 1112 when substrate 1102 is silicondioxide. Vaporized hydrofluoric acid may also be used to form cavity1112 when substrate 1102 is silicon dioxide. In an example wheresubstrate 1112 is silicon, a dry etching process using xenon difluoride(XeF₂) may be used to form cavity 1112. According to an embodiment,cavity 1112 has a depth between about 100 micrometers and about 250micrometers.

After formation of cavity 1112, mixer 1100 includes a suspendedpiezoelectric film stack 1101 that is anchored to substrate 1102 via oneor more anchor points 1114. FIG. 11D illustrates example top-down viewsof the same three mixer patterns (I, II, and III) discussed above withreference to FIG. 11B. These example views have been provided again toillustrate cavity 1112 from the top-down perspective, as well as theexample locations of anchor points 1114 for each mixer pattern.

FIG. 11E illustrates a fourth stage in the fabrication process of mixer1100, according to an embodiment. An opening 1116 is formed through athickness of substrate 1102 to provide either a fluidic port or anelectrical port. The electrical port may be used to make electricalconnection with either first electrode layer 1104 or second electrodelayer 1108. Opening 1116 may be formed using laser drilling or using wetetchants. For example, potassium hydroxide (KOH) may be used to etchthrough silicon while hydrofluoric acid may be used to etch throughsilicon dioxide. Dry etching processes such as deep reactive ion etching(DRIE) may be used as well.

Although a single opening 1116 is illustrated, it should be understoodthat a plurality of openings may be etched through a thickness ofsubstrate 1102 to form one or more fluidic inlets and one or morefluidic outlets. Additionally, one or more openings may be formed toprovide pathways for electrical connections to be made to both firstelectrode layer 1104 and second electrode layer 1108.

FIG. 12 illustrates an example integration of mixer 1100 withsemiconductor device 500, according to an embodiment. Prior to thebonding of mixer 1100, channel walls 1202 may be patterned overinterface layer 516 to form the walls of a microfluidic channel. Channelwalls 1202 may include a dielectric material that is patterned like aphotoresist using UV light, or that is dry etched. Channel walls 1202may include a polymer that is patterned using UV light.

In some embodiments, a bonding layer is deposited first over portions ofinterface layer 516 to provide a better bonding surface for channelwalls 1202. The bonding layer may include a dielectric materialdifferent than that of interface layer 516 such as, for example, silicondioxide.

After channel walls 1202 have been patterned, mixer 1100 may be bondedover channel walls 1202 to form an enclosed fluidic region 1204 thatdefines an inner volume of the microfluidic channel. The bonding may beperformed using an adhesive placed between substrate 1102 and channelwalls 1202. Heat and pressure may both be applied during the bondingprocess to improve the bond strength. According to an embodiment, mixer1100 is bonded such that is substantially aligned over opening 514.

Although not shown in the cross-section of FIG. 12 , fluid enters intofluidic region 1204 via an opening through substrate 1102. The fluidfills fluidic region 1204, which includes opening 514 patterned over abioFET sensor, and also fills cavity 1112 above piezoelectric stack1101. By applying a varying electric field across the electrodes abovepiezoelectric stack 1101, the piezoelectric material will mechanicallystrain in an oscillating fashion that effectively vibrates piezoelectricstack 1101 up and down as indicated by the double ended arrows. Thefrequency of the vibration depends on the alternating frequency of theapplied electric field, as well as the material properties of thepiezoelectric film. In one example, an electric field is applied acrosspiezoelectric stack 1101 having a DC offset between about 1 V and about100 V with an AC component between about 10 mV peak-to-peak and about1000 mV peak-to-peak at a frequency between about 1 kHz and about 100kHz. The presence of cavity 1112 allows for the vertical movement ofpiezoelectric stack 1101 and introduces turbulence into the fluid aroundpiezoelectric stack 1101. This fluid turbulence is also felt by thefluid around opening 514. Accordingly, the turbulence caused by mixer1100 can increase the efficiency of the bio-reactions occurring withinopening 514 above the bioFET sensor.

It should be understood that a single bioFET sensor is illustrated inFIG. 12 for clarity, but mixer 1100 may also be integrated in a similarmanner over a plurality of bioFET sensors. Additionally, opening 514 maystretch across more than one of the plurality of bioFET sensors (asdiscussed above with reference to FIG. 7B), such that the turbulencecreated by mixer 1100 improves the efficiency of the bio-reactionsoccurring over a plurality of bioFET sensors.

In some embodiments, channel walls 1202 are replaced by portions ofsubstrate 1102, such that substrate 1102 is directly bonded to interfacelayer 516. In some embodiments, the components of mixer 1100 may berecessed in substrate 1102 to form enclosed fluidic region 1204 uponbonding of substrate 1102 to interface layer 516.

Chemistry, Biology, and Interface

An example operation of dual gate back-side FET sensor 502 as a pHsensor will now be described with reference to FIG. 13 . Although theopening over dual gate back-side FET sensor 502 is illustrated in thefollowing figures as only being over channel region 508, it should beunderstood that the opening may stretch further to expose other dualgate back-side FET sensors, and that the size of the opening does notchange the bio-sensing operations described herein.

Briefly, a fluid gate 1302 is used to provide an electrical contact tothe “back gate” of dual gate back-side FET sensor 502. A solution 1301is provided over the reaction site of dual gate back-side FET sensor502, and fluid gate 1302 is placed within solution 1301. The pH of thesolution is generally related to the concentration of hydrogen ions [H⁺]in the solution. The accumulation of the ions near the surface ofinterface layer 516 above channel region 508 affects the formation ofthe inversion layer within channel region 508 that forms the conductivepathway between S/D regions 510. In some embodiments, a current I_(ds)flows from one S/D region to the other.

The current I_(ds) may be measured to determine the pH of solution 1301.In some embodiments, fluid gate 1302 is used as the gate of thetransistor during sensing while gate 506 remains floating. In someembodiments, fluid gate 1302 is used as the gate of the transistorduring sensing while gate 506 is biased at a given potential. Forexample, gate 506 may be biased at a potential between −2V and 2Vdepending on the application, while fluid gate 1302 is swept between arange of voltages. In some embodiments, fluid gate 1302 is biased at agiven potential (or grounded) while gate 506 is used as the gate of thetransistor (e.g., its voltage is swept across a range of potentials)during sensing. Fluid gate 1302 may be formed from platinum or may beformed from any other commonly used material(s) for reference electrodesin electrochemical analysis. An example of a reference electrode is asilver/silver chloride (Ag/AgCl) electrode, which has a stable potentialvalue of about 0.230 V.

FIG. 14A shows ions in solution binding to a surface of interface layer516. A top-most atomic layer of interface layer 516 is depicted as thevarious dangling [O⁻], [OH], and [OH₂ ⁺] bonds. As the ions accumulateon the surface, the total surface charge affects the threshold voltageof the transistor. As used herein, the threshold voltage is the minimumpotential between the gate and the source of a FET sensor that isrequired to form a conductive path of minority carriers between thesource and the drain of the FET sensor. The total charge also directlyrelates to a pH of the solution, as a higher accumulation of positivecharge signifies a lower pH while a higher accumulation of negativecharge signifies a higher pH.

FIG. 14B illustrates an example change in threshold voltage that resultsdue to different pH values in an n-channel FET sensor. As can beobserved in this example, a 59 mV increase in threshold voltage roughlysignifies an increase of one in the pH of the solution. In other words,one pH change results in total surface charge equivalent of 59 mV whenmeasured as the voltage required to turn ON the transistor.

Changing the threshold voltage of dual gate back-side FET sensor 502also changes a time it takes to form a conductive path between S/Dregions 510 for a given voltage input to either fluid gate 1302 or gate506. This time delay in “turning ON” the FET sensor may be quantifiedusing digital circuitry and used to determine an analyte concentration,according to some embodiments.

The apparatus, systems, and methods described in this application can beused to monitor interactions between various entities. Theseinteractions include biological and chemical reactions to detect targetanalytes in a test sample. As an example, reactions, including physical,chemical, biochemical, or biological transformations, can be monitoredto detect generation of intermediates, byproducts, products, andcombinations thereof. In addition, the apparatus, systems, and methodsof the present disclosure can be used to detect these reactions invarious assays as described herein, including, but not limited to,circulating tumor cell assays used in liquid biopsies and chelationassays to detect the presence of heavy metals and other environmentalpollutants. Such assays and reactions can be monitored in a singleformat or in an array format to detect, for example, multiple targetanalytes.

Referring to FIG. 15 , an example biosensing test is performed usingdual gate back-side sensing FET sensor 502. Probe DNA 1504 (an exampleof a capture reagent) is bound to interface layer 516 via a linkingmolecule 1502. Linking molecule 1502 may have a reactive chemical groupthat binds to a portion of interface layer 516. An example of linkingmolecules include thiols. Linking molecules may also be formed viasilanization of the surface of interface layer 516, or by exposing thesurface of interface layer 516 to ammonia (NH₃) plasma, to form reactiveNH₂ groups on the surface. The silanization process involvessequentially exposing the surface of interface layer 516 to differentchemicals to build up covalently-bound molecules on the surface ofinterface layer 516, as would be generally understood by a personskilled in the relevant art. Probe DNA 1504 represents single strandedDNA. Dual gate back-side sensing FET sensor 502 illustrated in FIG. 15is one bioFET sensor within a sensor array that would exist on a chip,according to some embodiments.

Probe DNA 1504 may be immobilized on interface layer 516 prior tosubjecting the FET sensor to fluid sample 1501. Fluid sample 1501 mayinclude the matching single stranded DNA sequence 1506 that bindsstrongly to its matching probe DNA 1504. The binding of additional DNAincreases the negative charge present on interface layer 516 anddirectly above channel region 508 of the FET sensor.

The DNA binding is illustrated conceptually in FIG. 16A. Here, probe DNAhaving nucleic acid sequence TCGA binds to its complementary matchedstrand having nucleic acid sequence AGCT. Any unmatched sequences doesnot hybridize with the probe DNA sequences. The binding of the matchingDNA increases the negative charge built up at the interface of interfacelayer 516. In the example illustrated in FIG. 16A, interface layer 516is hafnium oxide.

FIG. 16B illustrates a shift in the threshold voltage of the dual gateback-side sensing FET sensor when matching DNA is bound to the surfaceof interface layer 516. Briefly, voltage may be applied to fluid gate1302 until the FET sensor “turns on” and current flows between S/Dregions 510. In another example, voltage is applied to gate 506 to turnON the FET sensor while fluid gate 1302 is biased at a given potential.When more negative charge is present at interface layer 516 due tocomplementary DNA binding, a higher voltage is required to form theconductive inversion layer within channel region 508. Thus, according tosome embodiments, a higher voltage may be applied to fluid gate 1302, orgate 506, before the FET sensor conducts and I_(ds) current flows. Thisdifference in threshold voltage may be measured and used to determinenot only the presence of the target matching DNA sequence, but also itsconcentration. It should be understood that a net positive accumulatedcharge at interface layer 516 would cause the threshold voltage todecrease rather than increase. Additionally, the change in thresholdvoltage will have the opposite sign for an n-channel FET as compared toa p-channel FET.

Referring to FIG. 17 , another example biosensing test is performedusing dual gate back-side FET sensor 502. Probe antibodies 1704 (anotherexample of capture reagents) are bound to interface layer 516 vialinking molecules 1702. Linking molecules 1702 may have a reactivechemical group that binds to a portion of interface layer 516. A samplesolution 1701 may be provided over probe antibodies 1704 to determine ifthe matching antigens are present within sample solution 1701.

Referring to FIG. 18 , the binding process of matching antigens to probeantibodies 1704 is illustrated. Here, matching antigens will bind to theimmobilized probe antibodies while unmatched antigens will not bind.Similar to the DNA hybridization process described above, the matchingantigens will change the accumulated charge present at interface layer516. The shift in threshold voltage due to the accumulated charge frommatching antibodies binding to the probe antibodies is measured insubstantially the same way as discussed above with reference to FIG.16B.

FINAL REMARKS

Described herein are embodiments of a bioFET device that includes acommon opening over a plurality of dual gate back-side FET sensors.According to some embodiments, a bioFET device includes a semiconductorsubstrate having a first surface and an opposite, parallel secondsurface and a plurality of bioFET sensors on the semiconductorsubstrate. Each of the bioFET sensors includes a gate structure formedon the first surface of the semiconductor substrate and a channel regionformed within the semiconductor substrate beneath the gate structure andbetween source/drain (S/D) regions in the semiconductor substrate. Thechannel region includes a portion of the second surface of thesemiconductor substrate. The bioFET device also includes an isolationlayer disposed on the second surface of the semiconductor substrate. Theisolation layer has an opening that is positioned over the channelregion of more than one bioFET sensor of the plurality of bioFETsensors. The bioFET device also includes an interface layer disposed onthe channel region of the more than one bioFET sensor in the opening.

According to some embodiments, a method of fabricating a bioFET deviceincludes forming a plurality of gates on a first surface of asemiconductor substrate, where each of the plurality of gates is formedover a corresponding channel region in the semiconductor substrate. Themethod also includes forming S/D regions in the semiconductor substrateon either side of each channel region. The method also includes formingan opening in an isolation layer on a second surface of thesemiconductor substrate, the second surface being opposite and parallelto the first surface of a semiconductor substrate. Each of the channelregions in the substrate includes a portion of the second surface of thesemiconductor substrate, and the opening exposes a portion of the secondsurface of the semiconductor substrate that includes more than onechannel region. The method includes disposing an interface layer on thesecond surface of the semiconductor substrate within the opening.

According to some embodiments, a sensor array includes a semiconductorsubstrate having a first surface and an opposite, parallel secondsurface, and a plurality of bioFET sensors arranged in a matrix of rowsand columns on the semiconductor substrate. Each of the bioFET sensorsincludes a gate formed on the first surface of the semiconductorsubstrate and a channel region formed within the semiconductor substratebeneath the gate and between S/D regions in the semiconductor substrate.The channel region includes a portion of the second surface of thesemiconductor substrate. The sensor array also includes an isolationlayer disposed on the second surface of the semiconductor substrate andhaving an opening that extends along a length of at least one row of thematrix of rows such that the opening is positioned over the channelregion of more than one bioFET sensor of the plurality of bioFET sensorsin the at least one row. The sensor array also includes an interfacelayer disposed on the second surface of the semiconductor substratewithin the opening.

It is to be appreciated that the Detailed Description section, and notthe Abstract of the Disclosure section, is intended to be used tointerpret the claims. The Abstract of the Disclosure section may setforth one or more but not all exemplary embodiments of the presentdisclosure as contemplated by the inventor(s), and thus, is not intendedto limit the present disclosure and the subjoined claims in any way.

It is to be understood that the phraseology or terminology herein is forthe purpose of description and not of limitation, such that theterminology or phraseology of the present specification is to beinterpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present disclosure should not be limited byany of the above-described exemplary embodiments but should be definedin accordance with the subjoined claims and their equivalents.

What is claimed is:
 1. A method of fabricating a semiconductor device,the method comprising: forming a plurality of bio-field effecttransistor (bioFET) sensors on a semiconductor substrate with a firstsurface and a second surface opposite to the first surface, whereinforming each bioFET sensor of the plurality of bioFET sensors comprises:forming a gate on the first surface of the semiconductor substrate,wherein the gate is formed over a first channel region in thesemiconductor substrate, and forming a first pair of source/drain (S/D)regions in the semiconductor substrate on either side of the firstchannel region; forming a plurality of access FETs on the semiconductorsubstrate, wherein forming each access FET of the plurality of accessFETs comprises: forming an access gate on the first surface of thesemiconductor substrate, wherein the access gate is formed over a secondchannel region in the semiconductor substrate, and forming a second pairof S/D regions in the semiconductor substrate on either side of thesecond channel region; forming an isolation layer on the second surfaceof the semiconductor substrate; forming an opening in the isolationlayer, wherein the opening exposes the first channel regions of morethan one bioFET sensor of the plurality of bioFET sensors and does notexpose the second channel regions of the plurality of access FETs; anddisposing a continuous interface layer on the isolation layer and withinthe opening over the first channel regions of the more than one bioFETsensor, wherein the continuous interface layer extends over the secondchannel regions of the plurality of access FETs.
 2. The method of claim1, further comprising: wherein the first and second channel regionsinclude first and second portions, respectively, of the second surfaceof the semiconductor substrate.
 3. The method of claim 1, wherein theforming the each bioFET sensor further comprises forming a fluid gate onthe continuous interface layer.
 4. The method of claim 1, furthercomprising electrically coupling one of the first pair of S/D regions ofeach of the plurality of bioFET sensors with one of the second pair ofS/D regions of the plurality of access FETs.
 5. The method of claim 1,further comprising bonding a piezoelectric mixer over the openingthrough the isolation layer.
 6. The method of claim 1, wherein theforming the opening in the isolation layer comprises: performing a dryetch to decrease a thickness of an exposed region of the isolationlayer; and performing a wet etch to remove a remaining portion of theisolation layer within the exposed region after performing the dry etch.7. The method of claim 1, further comprising forming a microfluidicchannel over the plurality of access FETs and the plurality of bioFETsensors.
 8. A method of fabricating a semiconductor device, the methodcomprising: forming a plurality of bio-field effect transistor (bioFET)sensors on a substrate with a first surface and a second surfaceopposite to the first surface, wherein forming each bioFET sensor of theplurality of bioFET sensors comprises: forming first and second gates onthe first surface of the substrate, wherein the first and second gatesare formed over first and second channel regions in the substrate,forming a common source/drain (S/D) region between the first and secondchannel regions, and forming another S/D region coupled to a groundpotential; forming a plurality of access FETs on the substrate, whereinforming each access FET of the plurality of access FETs comprisesforming an access gate on the first surface of the substrate, whereinthe access gate is formed over a third channel region in the substrate;forming an isolation layer on the second surface of the substrate;forming an opening in the isolation layer, wherein the opening exposesthe first and second channel regions of more than one bioFET sensor ofthe plurality of bioFET sensors and does not expose the third channelregions of the plurality of access FETs; and disposing a first portionof an interface layer within the opening on the first and second channelregions of the more than one bioFET sensor and a second portion of theinterface layer on a portion of the isolation layer on the third channelregions of the plurality of access FETs.
 9. The method of claim 8,further comprising electrically coupling an S/D region of each accessFET of the plurality of access FETs to the common S/D region of eachbioFET sensor of the plurality of bioFET sensors.
 10. The method ofclaim 8, further comprising coupling a microfluidic channel over thesecond surface of the substrate such that a piezoelectric mixer disposedwithin the microfluidic channel is substantially aligned over theopening through the isolation layer.
 11. The method of claim 10, whereinthe forming the opening comprises forming the opening with a longestlength aligned with a direction along which a fluid, delivered by themicrofluidic channel, flows over the opening.
 12. The method of claim 8,wherein the forming the opening in the isolation layer comprises:performing a dry etch to decrease a thickness of an exposed region ofthe isolation layer; and performing a wet etch to remove a remainingportion of the isolation layer within the exposed region afterperforming the dry etch.
 13. A method, comprising: forming an array ofaccess transistors and shunt transistors arranged in an alternatingconfiguration in the array, wherein the forming the array of accesstransistors and shunt transistors comprises: forming each of the accesstransistors with an access gate on a first surface of a substrate and afirst channel region within the substrate beneath the access gate,forming each of the shunt transistors with a shunt gate on the firstsurface of the substrate and a second channel region within thesubstrate beneath the shunt gate, and forming a common source/drain(S/D) region between the first and second channel regions; forming anarray of bio-field effect transistor (bioFET) sensors on the substrate,wherein the forming the array the bioFET sensors comprises: forming anarray of gates on the first surface of the substrate, and forming anarray of S/D regions with a third channel region formed between eachpair of adjacent S/D regions in the array of S/D regions; forming anisolation layer on a second surface of the substrate; forming an openingin the isolation layer, wherein the opening exposes the third channelregions; and disposing an interface layer within the opening on thethird channel regions.
 14. The method of claim 13, wherein the formingthe each of the bioFET sensors comprises electrically coupling one ofthe S/D regions of the each of the bioFET sensors to the common S/Dregion.
 15. The method of claim 13, further comprising forming amicrofluidic channel on the interface layer.
 16. The method of claim 15,wherein the forming the opening comprises forming the opening with alongest length aligned with a direction along which a fluid, deliveredby the microfluidic channel, flows over the opening.
 17. The method ofclaim 13, wherein the forming the array of bioFET sensors comprisesforming the array of bioFET sensors on a portion of the substrate thatis different from a portion of the substrate on which the array of theaccess and shunt transistors is formed.
 18. The method of claim 13,wherein the forming the array of S/D regions comprises forming agrounded S/D region between each pair of adjacent bioFET sensors in thearray of bioFET sensors.
 19. The method of claim 13, further comprisingbonding a piezoelectric mixer over the opening through the isolationlayer.
 20. The method of claim 13, wherein the forming the opening inthe isolation layer comprises: performing a dry etch to decrease athickness of an exposed region of the isolation layer; and performing awet etch to remove a remaining portion of the isolation layer within theexposed region after performing the dry etch.